 We now know that cells interact with the surrounding environment through receptors on their cell surface that internalize specific molecules bound to it to influence the biology of the cell, which in some cases results in the secretion of other molecules. This very eloquent way of establishing a perfect harmony between a cell and its environment was only discovered in 1973, thanks to clever experiments from Joseph Goldstein and Michael Brown in their article titled, Identification of a Defect in the Regulation of HMGCoA Reductase Activity associated with overproduction of cholesterol, published in the Proceedings of the National Academy of Sciences. These scientists wanted to understand the mechanism causing a very peculiar disease called familial hypercholesterolemia, which is a genetic disease transmitted from parent to child in an autosomal dominant way, where one mutant copy of the gene was sufficient to cause disease. But no one knew what the disease gene was or what it did. In individuals with two mutant copies of the gene, the disease was much more severe, with death before the age of 30. But the more striking feature of the disease was the accumulation of low density lipoprotein LDL, also known as bad cholesterol, in pockets under the skin visible to the naked eye, in the blood and along the walls of arteries, causing heart disease in teenagers. Normally, each molecule of LDL has 1,500 molecules of cholesterol. LDL is under a form of negative feedback, meaning that when there is too much LDL in the blood, LDL blocks its own production in order to keep levels at a healthy state. When LDL levels are low, the proteins responsible for producing LDL are active, releasing the inhibition. In FH, LDL accumulates in the blood, seemingly without control. Being determined to find out what causes FH, these two scientists devised experiments in order to answer this very important question. Because LDL production was under negative feedback control, this gave the two scientists a clue that the regulation of LDL metabolism, the cycle regulating its synthesis and breakdown, may be to blame. First, they wondered if the LDL produced from FH patients was different from that produced in normal individuals, rendering the FH LDL unable to regulate cellular cholesterol production. They took LDL from the blood of an FH and a normal patient and put it into the surrounding media of cells in a petri dish. They measured whether the LDL from the two individuals had different regulatory effects on the production of cholesterol within the cell. But both samples of LDL were able to inhibit the production of additional LDL into the same extent, as you would expect from negative feedback regulation. So the LDL produced from FH patients was normal and able to block synthesis of additional cholesterol. In that case, how did LDL keep accumulating in these patients? Next, the scientists took cells from a 12-year-old girl suffering from FH and a healthy patient to grow them in a petri dish. They were curious to examine how the presence or absence of LDL in the surrounding media would affect the cell's production of cholesterol. When LDL was absent, FH and normal cells produced large amounts of cholesterol. But when LDL was added back, the normal cells stopped producing cholesterol while the FH cells kept up cholesterol production 80 times higher than normal cells, seemingly unaware that the levels of LDL in the media had changed. These experiments suggested that the cell itself was not able to respond to LDL present outside of the cell, breaking the communication between the inside and the outside of the cell. This important clue led to the discovery of the LDL receptor on the cell surface. LDL outside the cell binds to the LDL receptor, gets internalized and broken down to release cholesterol, which can then inhibit the cholesterol-producing enzyme from making more cholesterol. The LDL receptor then returns to the surface, making one round trip every 20 minutes. This is an example of receptor-mediated endocytosis. With a few important experiments, these two scientists discovered that FH is due to a mutation in the receptor for LDL, rendering it dysfunctional. Without this receptor, LDL outside the cell can't signal to the cholesterol machinery in the cell and stop its activity. Instead, LDL keeps being produced in the cell and accumulates everywhere in the body. This was the first example of receptor-mediated endocytosis, which has since been demonstrated to be an incredibly important and key regulatory mechanism for a cell to communicate with its environment. In this really great example, studying a rare genetic disease informed our understanding of a very important basic biological pathway, relevant to all cells and to everyone. Brown and Goldstein won the Nobel Prize in Physiology and Medicine in 1985 for their research. They run a joint laboratory and have been collaborating and sharing the discoveries with each other for over 40 years. This video has been provided to you by Eureka Science and iBiology, bringing the world's best biology to you.